Abstract The global objective of the Personalizing EmerGency/Acute therapeuticS Utilizing Systems biology (PEGASUS) Research Program is to improve drug effectiveness and safety in common acute care conditions. Drug therapy for acute conditions in the emergency department is only effective in 25-60% of cases. There is tremendous opportunity to improve acute therapeutics by implementing precision medicine programs in acute care settings. We will use phenotypic data from our electronic health record and link this data to pharmacogenomic and metabolomic data to discover new mechanisms of drug effectiveness and safety. Ultimately clinical, genomic, and metabolomic data will be integrated into predictive systems biology models to improve therapeutic success in acutely ill patients. The PEGASUS program is supported by the Rocky Mountain Biorepository and the Colorado Center for Personalized Medicine. Through the Maximizing Investigators' Research Award for Early Stage Investigators (MIRA-ESI) funding announcement PEGASUS will focus on common acute care conditions such as nausea, pain, and cardiovascular disease with eventual expansion to more uncommon drug safety conditions such as anaphylaxis and torsades de pointes. We utilize polymorphism in drug metabolizing enzymes, such as CYP2D6, as the hub of our models and use the biologic perturbations present in acute illness to identify new pathways, mechanisms, and genetic variants associated with drug safety and effectiveness in these common conditions. In the future, these models will be tested prospectively. Implementation of this systems biology approach to precision medicine will improve drug effectiveness and safety in acute conditions.